Treatment of hidradenitis suppurativa

ABSTRACT

Hidradenitis suppurativa can be treated by administering a pharmaceutical composition that includes a pharmaceutically acceptable carrier and a therapeutically effective amount of an agent that selectively binds IL-1α.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application claiming priority under35 U.S.C. 120 to U.S. patent application Ser. No. 16/540,543 filed onAug. 14, 2019, now U.S. patent application publication number US2019/0389946, which is a continuation-in-part application under 35 U.S.C. 111(a) of international patent application number PCT/IB2018/000209filed on Feb. 16, 2018 and designating the United States, which claimedthe priority of U.S. provisional patent application number 62/459,841filed on Feb. 16, 2017, the entire disclosures of each of the earlierapplications are hereby incorporated by reference herein.

FIELD OF THE INVENTION

The invention relates generally to the fields of medicine, dermatology,and immunology. More particularly, the invention relates to the use ofantibodies (Abs) which specifically bind interleukin-la (IL-1α) to treathidradenitis suppurativa.

BACKGROUND

Hidradenitis suppurativa (HS) is a chronic debilitating skin diseasewhere nodules appearing in areas rich in apocrine glands progressivelyswell until they rupture and release pus through the skin. Sinus tractformation and scars result. HS is typically treated with antibiotics andsurgery, but frequent relapse drastically impairs the patient's qualityof life.

SUMMARY

Disclosed herein is the discovery that an agent that specificallytargets IL-1α is useful for treating HS.

Accordingly, described herein are methods of reducing the severity of HSsymptoms in a human subject. These methods can include the step ofadministering to the subject a pharmaceutical composition including apharmaceutically acceptable carrier and an amount of an agent thatselectively binds IL-1α effective to reduce the number and/or size ofinflammatory lesions (e.g., nodule, abscesses, or draining fistulas),prevent their progression, reduce the pain caused by the lesions, orincrease the time until new exacerbations. The agent can be ananti-IL-1a antibody (Ab) such as a monoclonal antibody (mAb) (e.g., ofthe IgG1 isotype), a mAb that includes a complementarity determiningregion (CDR) of MABp 1, or MABp 1.

Another aspect of the invention features a method of reducing thesymptoms of HS in a human subject by administering to the subject apharmaceutical composition including a pharmaceutically acceptablecarrier and an amount of an anti-IL-1α Ab (or other agent thatspecifically and/or selectively binds IL-1α) effective to reduce thenumber and/or size of inflammatory lesions (e.g., nodule, abscesses, ordraining fistulas) in the subject by at least about 10% (e.g., at least8, 9, 10, 15, 17, 20, 30, 40, 50, 60, 70, 80, 90, or 100%) as measuredby any standard dermatological test.

The anti-IL-1α Ab can be a mAb such as an IgG1. The anti-IL-1α Ab can bethe mAb designated as MABp1 or a mAb that includes one or more (CDRs) ofMABp1. The pharmaceutical composition can be administered to the subjectby injection, infusion, subcutaneously, intravenously, intramuscularly,or intradermally. In the methods described herein, the dose can be atleast 0.25 (e.g., at least 0.2, 0.5, 0.75., 1, 2, 3, 4, or 5) mg/kg, andpreferably at between 1-20 mg/kg (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, or 20+/−0.1, 0.2, 0.3, 0.4, 0.5,0.6, 0.7, 0.8, or 0.9 mg/kg).

Unless otherwise defined, all technical terms used herein have the samemeaning as commonly understood by one of ordinary skill in the art towhich this invention belongs. Commonly understood definitions ofbiological terms can be found in Rieger et al., Glossary of Genetics:Classical and Molecular, 5th edition, Springer-Verlag: New York, 1991;and Lewin, Genes V, Oxford University Press: New York, 1994. Commonlyunderstood definitions of medical terms can be found in Stedman'sMedical Dictionary, 27^(th) Edition, Lippincott, Williams & Wilkins,2000.

As used herein, an “antibody” or “Ab” is an immunoglobulin (Ig), asolution of identical or heterogeneous Igs, or a mixture of Igs. An “Ab”can also refer to fragments and engineered versions of Igs such as Fab,Fab′, and F(ab′)₂ fragments; and scFv's, heteroconjugate Abs, andsimilar artificial molecules that employ Ig-derived CDRs to impartantigen specificity. A “monoclonal antibody” or “mAb” is an Ab expressedby one clonal B cell line or a population of Ab molecules that containsonly one species of an antigen binding site capable of immunoreactingwith a particular epitope of a particular antigen. A “polyclonal Ab” isa mixture of heterogeneous Abs. Typically, a polyclonal Ab will includemyriad different Ab molecules which bind a particular antigen with atleast some of the different Abs immunoreacting with a different epitopeof the antigen. As used herein, a polyclonal Ab can be a mixture of twoor more mAbs.

An “antigen-binding portion” of an Ab is contained within the variableregion of the Fab portion of an Ab and is the portion of the Ab thatconfers antigen specificity to the Ab (i.e., typically thethree-dimensional pocket formed by the CDRs of the heavy and lightchains of the Ab). A “Fab portion” or “Fab region” is the proteolyticfragment of a papain-digested Ig that contains the antigen-bindingportion of that Ig. A “non-Fab portion” is that portion of an Ab notwithin the Fab portion, e.g., an “Fc portion” or “Fc region.” A“constant region” of an Ab is that portion of the Ab outside of thevariable region. Generally encompassed within the constant region is the“effector portion” of an Ab, which is the portion of an Ab that isresponsible for binding other immune system components that facilitatethe immune response. Thus, for example, the site on an Ab that bindscomplement components or Fc receptors (not via its antigen-bindingportion) is an effector portion of that Ab.

When referring to a protein molecule such as an Ab, “purified” meansseparated from components that naturally accompany such molecules.Typically, an Ab or protein is purified when it is at least about 10%(e.g., 9%, 10%, 20%, 30% 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%,99.9%, and 100%), by weight, free from the non-Ab proteins or othernaturally-occurring organic molecules with which it is naturallyassociated. Purity can be measured by any appropriate method, e.g.,column chromatography, polyacrylamide gel electrophoresis, or HPLCanalysis. A chemically-synthesized protein or other recombinant proteinproduced in a cell type other than the cell type in which it naturallyoccurs is “purified.”

By “bind”, “binds”, or “reacts with” is meant that one moleculerecognizes and adheres to a particular second molecule in a sample, butdoes not substantially recognize or adhere to other molecules in thesample. Generally, an Ab that “specifically binds” another molecule hasa Ka greater than about 10⁵, 10⁶, 10⁷, 10⁸, 10⁹, 10¹⁰, 10¹¹, or 10¹²liters/mole for that other molecule. An Ab that “selectively binds” afirst molecule specifically binds the first molecule at a first epitopebut does not specifically bind other molecules that do not have thefirst epitope. For example, an Ab which selectively binds IL-1alphaspecifically binds an epitope on IL-1alpha but does not specificallybind IL-lbeta (which does not have the epitope).

A “therapeutically effective amount” is an amount which is capable ofproducing a medically desirable effect in a treated animal or human(e.g., amelioration or prevention of a disease or symptom of a disease).

Although methods and materials similar or equivalent to those describedherein can be used in the practice or testing of the present invention,suitable methods and materials are described below. All patents, patentapplications, and publications mentioned herein are incorporated byreference in their entirety. In the case of conflict, the presentspecification, including definitions will control. In addition, theparticular embodiments discussed below are illustrative only and notintended to be limiting.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a graph showing that 60% of patients allocated to treatmentwith MABp1 achieved positive HiSCR at week 12 compared to 10% of theplacebo group; and that the odds ratio (OR) for positive HiSCR underMABp1 was 13.50 (95% confidence intervals: 1.19-152.51; p=0.035).

FIG. 2 is a graph showing that the clinical efficacy of MABp1 wasmaintained until week 24 (i.e., 12 weeks after treatment was stopped),where no patients treated with placebo had a positive HiSCR score (0%)compared to four out of 10 patients (40%) treated with MABp1.

FIG. 3 is a graph showing the percent change of the total AN (sum ofinflammatory nodules and abscesses) count in all patients over the first24 weeks after the start of treatment with MABp1 or placebo.

FIG. 4 is a graph showing the percent change of the total AN count inpatients without previous exposure to anti-TNFα over the first 24 weeksafter the start of treatment with MABp1 or placebo.

FIG. 5 is a graph showing the percent change of the total AN count inpatients with previous anti-TNFα treatment failure over the first 24weeks after the start of treatment with MABp1 or placebo.

FIG. 6 is a graph showing the percent change in disease activity inpatients without previous exposure to anti-TNFα over the first 24 weeksafter the start of treatment with MABp1 or placebo.

FIG. 7 is a graph showing the percent change in visual analogue scale(VAS) in all patients over the first 24 weeks after the start oftreatment with MABp1 or placebo.

FIG. 8 is a graph showing the median time to new exacerbations inpatients without previous exposure to anti-TNFa over the first 24 weeksafter the start of treatment with MABp1 or placebo.

FIG. 9 is a graph showing the change in lesion depth in all patientsafter 12 weeks from the start of treatment with MABp1 or placebo.

FIG. 10 is a graph showing the change in lesion depth in patients withprevious anti-TNFα treatment failure after 12 weeks from the start oftreatment with MABp1 or placebo.

FIG. 11 is a graph showing the number of patients having at least a 20%reduction in lesion depth in patients treated with MABp1 or placebo.

FIG. 12 is a graph showing the number of patients having at least a 20%reduction in lesion depth in patients treated with MABp1 or placebo,wherein the patient populations were (i) those without previous exposureto anti-TNFα and (ii) those with previous anti-TNFα treatment failure.

FIG. 13 is a chart showing prior medical history of subjects in thestudy described in Example 1 below.

FIG. 14 is a chart showing baseline disease severity subjects in thestudy described in Example 1 below.

FIG. 15 is a flowchart summarizing a confirmatory study described inExample 2 below where bermekimab (MABp1) was formulated for subcutaneousadministration at 400 mg per week for 12 weeks.

FIG. 16 is a chart showing the baseline characteristics of studysubjects (anti-TNF failures vs. anti-TNF naives) who participated in thestudy described in Example 2.

FIG. 17 is a chart summarizing the results of the study described inExample 2.

FIG. 18 is a Study calendar of the study described in Example 2.

FIGS. 19-36 are graphs showing various results of the study described inExample 2.

DETAILED DESCRIPTION

The invention encompasses compositions and methods for reducing skininflammation in HS including ameliorating one or more symptoms of adermatological pathology in a subject. The below described preferredembodiments illustrate adaptation of these compositions and methods.Nonetheless, from the description of these embodiments, other aspects ofthe invention can be made and/or practiced based on the descriptionprovided below.

General Methodology

Methods involving conventional immunological and molecular biologicaltechniques are described herein. Immunological methods (for example,assays for detection and localization of antigen-Ab complexes,immunoprecipitation, immunoblotting, and the like) are generally knownin the art and described in methodology treatises such as CurrentProtocols in Immunology, Coligan et al., ed., John Wiley & Sons, NewYork. Techniques of molecular biology are described in detail intreatises such as Molecular Cloning: A Laboratory Manual, 2nd ed., vol.1-3, Sambrook et al., ed., Cold Spring Harbor Laboratory Press, ColdSpring Harbor, N.Y., 2001; and Current Protocols in Molecular Biology,Ausubel et al., ed., Greene Publishing and Wiley-Interscience, New York.Ab methods are described in Handbook of Therapeutic Abs, Dubel, S., ed.,Wiley-VCH, 2007. General methods of medical treatment are described inMcPhee and Papadakis, Current Medical Diagnosis and Treatment 2010,49^(th) Edition, McGraw-Hill Medical, 2010; and Fauci et al., Harrison'sPrinciples of Internal Medicine, 17th Edition, McGraw-Hill Professional,2008. Methods in dermatology are described in James et al., Andrews'Diseases of the Skin: Clinical Dermatology—Expert Consult, 11^(th) Ed.,Saunders, 2011; and Burns et al., Rook's Textbook of Dermatology, 8^(th)Ed., Wiley-Blackwell, 2010.

Treatment

The compositions and methods described herein are useful for treating HSin a mammalian subject by administering to the subject a pharmaceuticalcomposition including an amount of an anti-IL-1α Ab effective to improveat least one characteristic of the condition in the subject (e.g.,reduce the number and/or size of nodules, abscesses, or drainingfistulas or prevent their progression), or to improve one or more of thescores described below in the Examples section by at least 10% (e.g., atleast 10, 20, 30, 40, 50, 60, or 70%) or by at least one point (e.g., atleast 1, 2, 3, 4, 5, 6, 7, 8, or 9 points). The mammalian subject mightbe any that suffers from HS including human beings. Human subjects mightbe male, female, adults, children, seniors (65 and older), and thosewith other diseases. Particularly preferred subjects are (i) those whosedisease has progressed or failed to respond after treatment with otheranti-inflammatory (e.g., TNFα inhibitors) or anti-microbial agents; (ii)those with a familial history of HS; (iii) those in which otheranti-inflammatory (e.g., TNFα inhibitors) or anti-microbial agents arenot suitable; and (iv) those with higher than 100, 200, 300, 400, 500,or 1000 pg/ml of IL-1α in pus taken from their lesions. Subjects whohave developed a human anti-human antibody response due to prioradministration of therapeutic antibodies are preferred when theanti-IL-1α Ab is a true human Ab (e.g., one that is naturally expressedin a human subject) such as MABp1.

Antibodies and other Agents that Target IL-1α

Any suitable type of Ab that specifically binds IL-1α and reduces acharacteristic of HS in a subject might be used. For example, theanti-IL-1α Ab used might be mAb, a polyclonal Ab, a mixture of mAbs, oran Ab fragment or engineered Ab-like molecule such as an scFv. The Ka ofthe Ab is preferably at least 1+10⁹ M⁻¹ or greater (e.g., greater than9×10¹⁰M⁻¹, 8×10¹⁰M⁻¹, 7×0¹⁰M⁻¹, 6×10¹⁰M⁻, 5×10¹⁰M⁻¹, 4×10¹⁰M⁻¹,3×10¹⁰M⁻¹, 2×10¹⁰M⁻¹, or 1×10¹⁰M⁻¹). In a preferred embodiment, theinvention utilizes a fully human mAb that includes (i) anantigen-binding variable region that exhibits very high binding affinity(e.g., at least nano or picomolar) for human IL-1α and (ii) a constantregion. The human Ab is preferably an IgG1, although it might be of adifferent isotype such as IgM, IgA, or IgE, or subclass such as IgG2,IgG3, or IgG4. One example of a particularly useful mAb is MABpl, anIL-la-specific IgG1 mAb described in U.S. Pat. No. 8,034,337B2 issued onOct. 11, 2011. Other useful mAbs are those that include at least one butpreferably all the CDRs of MABpl. CDRs may be determined according toknown methods such as described in Ofran et al., J. Immunol., 181:6230,2008; and Antibody Engineering Volume 2, 2d edition, Konterman and Dubel(eds), Springer, 2010. Abs that specifically binds IL-1α and methods oftheir manufacture are described in more detail in, e.g., U.S. Pat. No.9,545,411.

While the IL-1α specific Abs described above are preferred for use inthe methods described herein, in some cases, other agents thatspecifically target IL-1α might be used so long as their administrationleads to improvement of a characteristic of HS. These other agents mightinclude vaccines that cause the production of anti-IL-1α Abs, proteinsor peptides that bind IL-1α, and small organic molecules whichspecifically target IL-1α. Those that do not specifically bind IL-1β arepreferred because the use of such agents have been reported to worsenthe symptoms of HS (e.g., Tekin et al., Indian J Dermatol VenereolLeprol 2017; 83:615-7), and others have reported that IL-1β promoteshealing and repair (e.g., Bersudsky et al., Gut. 2014 April;63(4):598-609).

Pharmaceutical Compositions and Methods

The anti-IL-1α Ab compositions (and other agents that specificallytarget IL-1α) may be administered in pharmaceutically acceptablecarriers (e.g., sterile saline), that are selected on the basis of modeand route of administration and standard pharmaceutical practice. A listof pharmaceutically acceptable carriers, as well as pharmaceuticalformulations, can be found in Remington's Pharmaceutical Sciences, astandard text in this field, and in USP/NF. Other substances may beadded to the compositions and other steps taken to stabilize and/orpreserve the compositions, and/or to facilitate their administration toa subject.

For example, the Ab compositions might be lyophilized (see Draber etal., J. Immunol. Methods. 181:37, 1995; and PCT/US90/01383); dissolvedin a solution including sodium and chloride ions; dissolved in asolution including one or more stabilizing agents such as albumin,glucose, maltose, sucrose, sorbitol, polyethylene glycol, and glycine;filtered (e.g., using a 0.45 and/or 0.2 micron filter); contacted withbeta-propiolactone; and/or dissolved in a solution including amicrobicide (e.g., a detergent, an organic solvent, and a mixture of adetergent and organic solvent.

The Ab compositions may be administered to animals or humans by anysuitable technique. Typically, such administration will be parenteral(e.g., intravenous, subcutaneous, intramuscular, or intraperitonealintroduction). The compositions may also be administered directly to thetarget site (e.g., the skin) by, for example, topical application. Othermethods of delivery, e.g., liposomal delivery or diffusion from a deviceimpregnated with the composition, are known in the art. The compositionmay be administered in a single bolus, multiple injections, or bycontinuous infusion (e.g., intravenously or by peritoneal dialysis).

A therapeutically effective amount is an amount which is capable ofproducing a medically desirable result in a treated animal or human. Aneffective amount of anti-IL-1α Ab compositions is an amount which showsclinical efficacy in patients as measured by the improvement in one ormore symptoms of skin inflammation. As is well known in the medicalarts, dosage for any one animal or human depends on many factors,including the subject's size, body surface area, age, the particularcomposition to be administered, sex, time and route of administration,general health, and other drugs being administered concurrently.Preferred doses range from between 1-20 mg/kg body weight (e.g., 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or20+/−0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9 mg/kg body weight).In some cases, a single dose is effective at resolving an episode ofskin inflammation. In other cases, doses may be given repeatedly, e.g.,semi-weekly, weekly, bi-weekly, tri-weekly, semi-monthly, once everythree weeks, monthly, bi-monthly, or as needed (if lesions recur).

Combination Treatment

HS patients treated with an agent that selectively binds IL-1α can alsobe administered other agents. For example, such patients can be treatedwith corticosteroids, retinoids, resorcinol, hormones, and biologicssuch as adalimumab or infliximab. Antimicrobials might also be used. Inparticular, antibiotics or other agents that target S. aureus can beused in those patients having or suspected of having S. aureuscolonization or infection in one or more HS lesions. The use ofantibodies that opsonize S. aureus are believed to be particularlyuseful. Preferred anti-S. aureus for this use are those having Fabregion paratopes that specifically bind to S. aureus protein A (SpA) andFc regions that do not bind SpA such that there are capable of mediatingopsinization of S. aureus bacteria despite S. aureus's expression ofantibody-neutralizing SpA. These are described in U.S. Pat. No.9,416,172 (e.g., the antibody designated PA8-G3 therein).

EXAMPLES Example 1

A double-Blind, Randomized, Placebo-Controlled Clinical Trial of theSafety and efficacy of MABp1, a True Human™ antibody targetinginterleukin-1α, in patients with HS. HS patients were screened fromthose who are currently under follow-up. Inclusion criteria were:written informed consent provided by the patient; age 18 years or older;diagnosis of HS; HS of Hurley II or III stage disease or rapidlyprogressive HS of Hurley I stage; presence of 3 or more inflamed nodulesconsistent with HS in the body; at least one of the following: a)previous failure of treatment with any anti-TNFa, regimen; b) previousrelapse under treatment with any anti-TNFα, regimen; or c) unwillingnessto receive subcutaneous adalimumab treatment.

Exclusion criteria were: history of systemic lupus erythematosus, ofrheumatoid arthritis or of seronegative inflammatory arthritis;treatment with any biologicals or investigational agents within the last4 weeks (or 5 half-lives, whichever is longer); history of severeallergic or anaphylactic reactions to human, humanized, chimeric, ormurine monoclonal antibodies; administration of any live (attenuated)vaccine over the last 4 weeks; history of recurrent vein thrombosis orembolism compatible with anti-cardiolipin syndrome; any present seriousbacterial infection namely pneumonia, endocarditis, acute pyelonephritisand intraabdominal infection; hepatic dysfunction defined as any valueof transaminases, of γ-glutamyl transpeptidase or of bilirubin>2×uppernormal limit; history of hematological or solid tumor malignancy,arterial hypertension, liver cirrhosis, HIV infection, and hepatitisvirus B or C infection; history of episodes mimicking demyelinatingdisorders or a definite diagnosis of multiple sclerosis; any creatininevalue above 1.5 mg/dl; intake of corticosteroids defined as daily intakeof prednisone or equivalent more than 1 mg/kg for the last three weeks;neutropenia defined as <1000 neutrophils/mm3; pregnancy or lactation;history of tuberculosis (latent or active); major surgery within 28 daysprior to Day 0.

Diagnosis of HS was based on the following criteria, set by the 2ndConference of the HS foundation in San Francisco: disease onset afterpuberty; involvement of at least two areas of the skin rich in apocrineglands; and history of recurrent painful boils without/with drainage ofpus from the affected areas. Once a patient was considered eligible forthe study the following procedures were performed: thorough study ofrecord-history and medications; thorough physical examination; skintuberculin test (any diameter below 5 mm is considered negative); chestX-ray; serology for human immunodeficiency virus (HIV), for hepatitis Bvirus (HBV) and for hepatitis C virus (HCV); serum creatinine; and liverbiochemistry. Only patients within normal were enrolled in the study.Patients were randomly 1:1 assigned to receive either placebo or MABp1(XBiotech USA, Inc.) intravenously. The randomization sequence was builtby an independent biostatistician. The investigational drug or matchedplacebo was administered intravenously with a one-hour infusion every 14days (+/−1 day) for 12 weeks, i.e., at week 0 (baseline), week 2, week4, week 6, week 8, week 10 and week 12 for a maximum of seven infusions.The dose of MABp1 was 7.5 mg/kg.

XILONIX™, is a sterile injectable liquid formulation of 50 mg/mL MABp1in a stabilizing isotonic buffer (pH 6.4). Each 10-mL serum vialcontains 6 ml of the formulation, and is sealed with a 20-mm greybromobutyl stopper and flip-off aluminum seal. Product was stored at2-8° C., with excursions to room temperature permitted. The exactcomposition of the drug product is shown below:

Composition of the Final Drug Product Ingredient Grade ManufacturerConcentration MABp1 antibody GMP XBiotech 50 mg/ml sodium phosphatedibasic compendial JT Baker 12 mg/ml citric acid monohydrate compendialJT Baker 2 mg/ml Trehalose•2H2O (high- compendial Ferro- 60 mg/ml puritylow endotoxin) Pfanstiehl polysorbate 80 compendial JT Baker 0.2 mg/mlPhosphoric acid, to compendial JT Baker 0.04 mg/ml adjust pH water forinjection compendial Microbix —

The placebo product was manufactured following the same procedures andbatch records used to manufacture the MABp1 drug product. The placebodosage form is a sterile isotonic formulation buffer at pH 6.2-6.5. Each10-ml Type I borosilicate glass serum vial contains 6 mL of theformulation buffer, and is sealed with a 20-mm Daikyo Flurotec butylrubber stopper and flip-off aluminum seal. The product was storedupright at 2-8° C., with excursions to room temperature permitted. Theexact composition of the Placebo Product is shown in the table below:

Composition of Placebo Product Ingredient Grade ManufacturerConcentration trehalose dihydrate compendial Ferro-Pfanstiehl 60 mg/ml(USA) sodium phosphate compendial JT Baker (USA) 12 mg/ml dibasic citricacid compendial JT Baker (USA) 2 mg/ml monohydrate Polysorbate 80compendial JT Baker (USA) 0.2 mg/ml Phosphoric acid, to compendial JTBaker 0.04 mg/ml adjust pH water for injection compendial IrvineScientific q.s. (USA)

XILONIX·8 was diluted in a 100-mL bag of normal saline prior toinfusion. The following calculations were used to determine the volumeof drug product to be diluted for each study subject:

${50\mspace{14mu} {{mg}/{ml}}\mspace{14mu} {drug}\mspace{14mu} {product}},{{7.5\mspace{14mu} {{{mg}/{kg}}\mspace{14mu} {dose}:{{Volume}\mspace{14mu} {of}\mspace{14mu} {drug}\mspace{14mu} {product}\mspace{14mu} {to}\mspace{14mu} {be}\mspace{14mu} {diluted}}}} = {{Vd} = \frac{\left( {{Body}\mspace{14mu} {Weight} \times {Dosage}} \right)}{50\mspace{14mu} {{mg}/{ml}}}}}$(Body  Weight  was  rounded  to  the  nearest  whole  number)${{Example}\mspace{14mu} {for}\mspace{14mu} 70\mspace{14mu} {kg}\mspace{14mu} {Subject}\mspace{14mu} {at}\mspace{14mu} 7.5\mspace{14mu} {{mg}/{{kg}:{Vd}}}} = \frac{\left( {70\mspace{14mu} {kg} \times 7.5\mspace{14mu} {{mg}/{kg}}} \right)}{50\mspace{14mu} {{mg}/{mL}}}$Vd = 10.5  mL  (round  to  one  decimal  place)

The calculated volume (Vd) was withdrawn from the subject's assignedvial(s) using a suitable syringe. The same amount of saline as thecalculated drug was removed from the 100-ml bag. The calculated volumewas then injected into the 100-mL IV bag of normal saline (0.9% NaCl),resulting in a final total volume of 100 ml. The drug product was thenmixed by gently inverting the bag ten times. After priming the infusionset lines, the delivery pump was programmed to deliver 100 mL of thediluted drug product over a 1-hour period (60+/−15 minutes), with thesubject being monitored for signs of an infusion reaction. Patients'visits occurred at week 0, at week 2, at week 4, at week 6, at week 8,at week 10, at week 12, at week 16, at week 20 and at week 24. At everyvisit the following procedures were performed.

Visits 1 2 3 4 5  6  7  8  9 10 Weeks 0 2 4 6 8 10 12 16 20 24 DQLI x —— — — x — — x Physical examination x x x x x x x x x x HiSCR x x x x x xx x x x PGA x x x x x x x x x x Disease activity x x x x x x x x x xModified Sartorius x x x x x x x x x x VAS for disease x x x x x x x x xx VAS for pain x x x x x x x x x x Photo x — — — — — x — — x Bloodsampling x — — — — — x — — x DQLI: Dermatology Quality of Life IndexHiSCR: Hidradenitis Suppurativa Clinical Response score PGA: Physicians’Global Assessment VAS: Visual Analogue Scale

Patients were asked to provide an assessment of the severity of theirdisease using the visual analogue scale (VAS) in mm. They were told that0 represents no disease activity and 100 the worst disease activity theyever felt. Patients were asked to provide one score for their overallimpression about their disease and another score about the physical painthey feel. The investigators asked the patient to provide the frequencyof the exacerbation of his disease and the pain felt at the affectedsites. Patients were given the below DLQI score and they were asked tofill it out only at week 0, at week 12 and at week 24.

The Dermatology Quality of Life Index (DQLI). Each question is scoredfrom 0 (absence) to 3 (intense problem)

Question Score 1. How itchy, sore, painful or stinging has your skincondition been? 2. How embarrassed or self-conscious have you beenbecause of your skin? 3. How much has your skin interfered with yougoing shopping or looking after your home or garden? 4. How much hasyour skin influenced the clothes you wear? 5. How much has your skinaffected your social or leisure activities? 6. How much has your skinmade it difficult for you to do any sport? 7. Has your skin preventedyou from working or studying? 8. How much has your skin created problemswith your partner or any of your close friends or relatives? 9. How muchhas your skin caused any sexual difficulties? 10. How much of a problemhas the treatment for your skin been?

The investigators counted the following from each individually affectedarea and took a photo of that area: the number of fistulas; the numberof nodules or abscesses; the number of scars; their impression about thedegree of inflammation scored from 0 to 3 as follows: 0, absent, 1,mild; 2, moderate; 3, intense; the two largest dimensions of each lesionin mm. Based on the above the following two scores were assessed at eachvisit: Hidradenitis Suppurativa Clinical Response (HiSCR) score andPhysicians' Global Assessment (PGA) score. For HiSCR, patients weredefined as achievers or non-achievers. The probability of achieving apositive HiSCR score was starting from the second visit and it wasdefined as a >50% reduction in inflammatory lesion count (sum ofabscesses and inflammatory nodules), and no increase in abscesses ordraining fistulas in HS when compared with baseline. For PGA, this scorewas classified as: a) clear when the total number of abscesses is 0, thetotal number of draining fistulas is 0, the total number of inflammatorynodules is 0 and the total number of non-inflammatory nodules is 0; b)minimal when the total number of abscesses is 0, the total number ofdraining fistulas is 0, the total number of inflammatory nodules is 0and there is presence of non-inflammatory nodules; c) mild when thetotal number of abscesses is 0, the total number of draining fistulas is0, and the total number of inflammatory nodules is 1-4 or when there ispresence of one abscess or draining fistula and absence of anyinflammatory nodule; d) moderate when the total number of abscesses is0, the total number of draining fistulas is 0 and the total number ofinflammatory nodules is up to 5 or when there is presence of one abscessor draining fistula and up to one inflammatory nodule; e) severe whenthe total number of abscesses or draining fistulas is 2-5 and the totalnumber of inflammatory nodules is 5-10; and f) very severe when thereare more than 5 abscesses or draining fistulae.

Disease activity. This is defined as the sum of scores of all affectedareas of each patient. Each area was evaluated by the following formula:(multiplication of the two largest diameters in each affected area inmm)×(the degree of inflammation of each lesion).

The modified Sartorius score. This is the sum of separate scoring foreach affected area using the data recorded as follows: a) 3 points peranatomical region involved; b) 6 points for each fistula and 1 point foreach nodule or abscess; c) 1 point when the longest distance between tworelevant lesions in each affected area is <5 cm; 3 points when it is5-10 cm; and 9 points when it is >10 cm; and d) 9 points when there isno clear separation of lesions from adjacent normal skin and 0 pointswhen there is.

The efficacy of MABp1 in patients with moderate to severe HS by HiSCRscoring was assessed by the difference of achievement of positive HiSCRscore between the treatment group and the comparator placebo group atweek 12. The long-term efficacy of MABp1 in patients with moderate tosevere HS by positive HiSCR scoring was assessed by the difference ofachievement of HiSCR score between the treatment group and thecomparator placebo group at week 24. Analysis was done separately forpatients with previous failure or relapse under adalimumab and forpatients without previous adalimumab treatment. The short-and long-termefficacy of MABp1 in patients with moderate to severe HS was assessed bythe comparisons of all used scoring systems (HiSCR, PGA, DLQI, diseaseactivity, VAS for disease, VAS for pain and modified Sartorius score) onall study visits. Analysis was also done separately for patients withprevious failure or relapse under adalimumab and for patients withoutprevious adalimumab treatment. The effect of MAbp1 on the time to newexacerbation was assessed by comparing the time to new exacerbation fromweek 0 between the two groups of treatment. Analysis was done separatelyfor patients with previous failure or relapse under adalimumab and forpatients without previous adalimumab treatment. Comparisons of HiSCRbetween the two study groups was done by the Fischer's exact test.Comparisons of severity score for each study visits were done bynon-parametric statistics. Comparison of the time to new exacerbationbetween the two groups was done by the log-rank test.

Results. FIGS. 1-12 show the results of the study. Patients treated withMABp1 achieved a significantly greater rate of positive HiSCR scoresthan comparators. Treatment with MABp1 was associated with significant:increased positive HiSCR scoring at week 24; decreased total AN count(more pronounced in patients without previous anti-TNF exposure);decreased VAS for the disease; prolongation of the time to newexacerbations in patients without previous anti-TNF exposure; andsignificant decrease of US depth of total body lesions (more pronouncedin patients without previous anti-TNF failure).

Example 2

The topline results from an investigator sponsored randomized Phase 2study evaluating MABp1 as a treatment for Hidradenitis Suppurativa (HS)showed that study met its primary endpoint, demonstrating significantimprovement of HS patients compared to control after 12 weeks of therapy(response rate of 60% vs 10%, respectively (p=0.035)).

The 20 patient double-blind, placebo-controlled study was designed toevaluate the safety and efficacy of MABp1, a True Human^(TM) antibodytargeting interleukin-1 alpha (IL-1a), in patients with HS not eligiblefor anti-TNFa therapy. Patients were randomized 1:1 to receive eitherMABp1 or placebo every 2 weeks for 12 weeks. Patients in the studyunderwent primary assessment of efficacy using Hidradenitis SuppurativaClinical Response (HiSCR) scores at 12 weeks, continued by a follow upphase to assess time to relapse after an additional 12 weeks withouttherapy. Efficacy measures include assessment of HiSCR scores, avalidated method for evaluating efficacy in HS patients, as well asquality of life assessment and ultrasonographic evaluation.

Sixty percent of patients allocated to treatment with MABp1 achievedpositive HiSCR at week 12 compared to 10% of the placebo group (FIG. 1).The odds ratio (OR) for positive HiSCR under MABp1 was 13.50 (95%confidence intervals: 1.19-152.51; p=0.035). The total AN count which isthe basic component of the HiSCR score was decreased over the first 12weeks under treatment (FIG. 3). The clinical efficacy of MABp1 wasmaintained until week 24, i.e., 12 weeks after treatment was stopped. Atthat time point, as shown in FIG. 2, no patients treated with placebohad a positive HiSCR score (0%) compared to four out of 10 patients(40%) treated with MABp1. Treatment with MABp1 was also accompanied bybetter patient-reported outcomes. Decrease of the visual analogue scale(VAS) was found in 30% (three out of 10) and in 70% (seven out of 10)allocated to placebo and MABp1 respectively. Sub-analysis showed thatthis was 40% (two out of five) and 33.3% (one out of three) respectivelyamong anti-TNFs naive patients and 20% (one out of five) and 85.7% (sixout of seven) among patients failing previous treatment with anti-TNFs.The median time to the first HS exacerbation was seven weeks in theplacebo group and 11 weeks in the MABp1 group. This time did not differsignificantly between groups (log-rank: 1.98, p=0.159). However, whensub-analysis was done among anti-TNFs naive patients, it was found thatthe median time until a new HS exacerbation was 4 weeks with placebotreatment and 18.5 weeks with MABp1 treatment (log-rank test: 4.46;p=0.035; see FIG. 8). A decrease in disease activity was found in allpatients treated with MABp1 and who achieved positive HiSCR at weeks 12and 24. A decrease of at least two of the assessed scores i.e.Physicians' Global Assessment (PGA), disease activity, modifiedSartorius score, VAS for pain, and dermatology life quality index (DLQI)at week 12 was found in 40% of patients allocated to placebo and 80% ofpatients allocated to MABp1 (80%) (OR=14.50; 95% confidence intervals:0.96-218.99; p=0.054). Sub-analysis showed that this was 60% (three outof five) and 100% (three out of three) respectively among anti-TNFsnaive patients and 20% (one out of five) and 71.4% (five out of seven)among patients failing previous treatment with anti-TNFs. Significantchanges in variables for skin ultrasound included total lesionvascularity and total lesion depth, which is the sum of the grading ofvascularity and the sum of the greatest depth of all involved skinareas, respectively. Both variables were decreased after treatment withMABp1 (FIGS. 9-12). More than 20% decrease of total lesion depth wasselected as a cut-off point, and it was found in 22.2% of patientsallocated to placebo compared to 77.8% of patients treated with MABp1(OR=12.25; 95% confidence intervals 1.33-113.06; p=0.027). The effectwas pronounced among patients who have failed previous anti-TNFs (FIG.10). Significant improvement in the elasticity of the affected areas wasalso noted.

Serum IL-1α was below the lower limit of detection in the sera sampledfrom all patients both before and at the end of blind treatment. Pus wassampled before treatment from six patients allocated to placebo andseven patients allocated to MABpl. Mean±SE concentrations of IL-1α were697.2±440.4 pg/ml and 772.0±221.7 pg/ml respectively (p=0.412 by theMann-Whitney U test). Treatment with MABp1 was accompanied by decreaseof serum IL-8. More than 30% decrease of IL-8 on week 12 was selected asa cut-off point. The OR for this cut-off point by MABp1 was 13.50 (95%confidence intervals: 1.19-152.51; p=0.035). This was consistent withchange in levels of IL-8 produced from whole blood stimulated withheat-killed Staphylococcus aureus, which was significantly lower amongpatients treated with MABp1 than patients treated with placebo. Thecapacities of whole blood to produce both IL-1α and human β-defensin(hBD)-2 were positively associated among placebo-treated patients. Amongthe same patients, the capacity for hBD-2 production was negativelycorrelated with the change of the skin depth of the lesions atultrasound. These correlations ceased to exist among MABp1-treatedpatients, which suggested an hBD-2-associated mode of action of MABp1 inHS that was mediated through the inhibition of IL-la.

Safety—no study drug related adverse events or serious adverse eventsoccurred in the study.

Analysis of the data using the iHS4 score for all 20 patients who wererandomized to receive either placebo or MABp1 therapy in the Phase 2double-blind study was performed. At least a 30% decrease of the iHS4score from the baseline at week 12 was associated with 100% sensitivityfor positive HiSCR score (the efficacy measure used in the phase 2study). This change was found in one (10%) and in four (40%) patientsallocated to placebo and MABp1, respectively (p=0.046).

Patients that had originally been allocated to placebo in the Phase 2study were allowed to receive treatment with the MABp1 antibody therapyin a so called open label extension (OLE) study. Seven of 10 patientsthat had originally received placebo were treated with MABp1 for 12weeks. Main endpoints used in the OLE included safety and HiSCR score atthe end of the 12 week treatment. At the conclusion of thedouble-blinded study, only one patient (1 of 10, or 10%) receivingplacebo had achieved HiSCR. During the OLE, five patients (5 of 7, or71.4%) achieved the HiSCR response (p=0.035). There was a total of 24 HSexacerbations during the blinded portion of the study compared to just 1exacerbation during the OLE phase.

“The overall response rate observed in the data is, in my opinion,groundbreaking for the treatment of HS,” Dr. Giamarellos-Bourbouliscommented, “I am truly encouraged by these results and very much lookforward to the future use of MABp1 as a treatment for this devastatingcondition.”

Example 2

a Phase II Open Label, Study of Subcutaneously Administered Bermekimab(MABp1) in Patients with Moderate to Severe Hidradenitis Suppurativa.Bermekimab was formulated for subcutaneous administration at 400 mg perweek for 12 weeks as shown in FIG. 15. The baseline characteristics ofstudy subjects (anti-TNF failures vs. anti-TNF naives) is shown in FIG.16. A summary of the results is presented in FIG. 17 where Group A issubjects who previously failed anti-TNF treatment and Group B issubjects never administered anti-TNF treatment. The Study calendar isshown in FIG. 18. Detailed results of the study are shown in FIGS.19-36.

Other Embodiments

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

What is claimed is:
 1. A method of treating hidradenitis suppurativa in a human subject having lesions associated with hidradenitis suppurativa, the method comprising the step of administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an amount of an anti-IL-1a antibody effective to treat a symptom of hidradenitis suppurativa in the subject.
 2. The method of claim 1, wherein the anti-IL-1a antibody is a monoclonal antibody.
 3. The method of claim 2, wherein the monoclonal antibody is an IgG1.
 4. The method of claim 3, wherein the monoclonal antibody is MABp1.
 5. The method of claim 1, wherein the subject's HiSCR score is improved after administration of the pharmaceutical composition.
 6. The method of claim 1, wherein the median size of the subject's hidradenitis suppurativa lesions is reduced after administration of the pharmaceutical composition.
 7. The method of claim 1, wherein the subject's pain associated with the subject's hidradenitis suppurativa lesions is reduced after administration of the pharmaceutical composition.
 8. The method of claim 1, wherein the subject's time to new hidradenitis suppurativa lesions is increased after administration of the pharmaceutical composition.
 9. The method of claim 1, wherein the hidradenitis suppurativa in the human subject has failed to resolve after treatment with tumor necrosis factor alpha inhibitors.
 10. The method of claim 1, further comprising the step of administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an anti-S. aureus antibody.
 11. The method of claim 10, wherein the anti-S. aureus antibody comprises a Fab region paratope that specifically binds to S. aureus protein A (SpA) and an Fc region that does not specifically bind SpA. 